»
Pharmaceutical Chemistry

The benzomorphans are prepared synthetically and thus result in several stereoisomers. The active benzomorphans are those that have the equivalent bridgehead carbons in the same absolute configuration of morphine (carbons 9, 13, and 14 of morphine). The only benzomorphan in clinical use is pentazocine, which is prepared as the 2(R), 6(R), 11(R) enantiomer (Chemical Abstracts numbering).74 Pentazocine is a mixed agonist antagonist displaying differing intrinsic activity at the opioid receptor...

Sitosterol is a plant sterol, whose structure is identical with that of cholesterol, except for the substituted ethyl group on C-24 of its side chain. Although the mechanism of its hypolipidemic effect is not clearly understood, it is suspected that the drug inhibits the absorption of dietary cholesterol from the gastrointestinal tract. Sitosterols are absorbed poorly from the mucosal lining and appear to compete with cholesterol for absorption sites in the intestine. responsible...

Mitomycin C (Fig. 10.24) was isolated from Streptomyces caespitosus in 1958 by Japanese workers and is considered the prototype of the bioreductive alkylating agents.137139 Mitomycin is sometimes included as an alkylating agent but is included here because it is a naturally occurring material. The drug contains what would appear to be reactive functionalities, including the quinone and aziridine functionalities, both or which would be thought to be susceptible to nucleophilic attack however,...

In spite of the long history of vaccines, only a few adjuvants and vaccine delivery systems have been licensed for human use. There are several reasons for this. Vaccines based on live-attenuated organisms are invasive and are efficiently delivered to APCs. Pattern-recognized components of the cellular pathogens are recognized by the innate immune system and trigger an innate response. With the trend of using subunit vaccines and isolated antigens, immune potentiators and delivery systems have...

Synthetase, and the biologically generated triphosphate competitively inhibits thymidine triphosphate incorporation into DNA by DNA polymerase. In addition, trifluridine in its triphosphate form is incorporated into viral and cellular DNA, creating fragile, poorly functioning DNA. Trifluridine is approved in the United States for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV types 1 and 2. Topical trifluridine shows some efficacy in patients with...

Kappa receptors are primarily found in the limbic, brain stem, and spinal cord.34 The K-receptor shows less structural homology to the -receptor than the S-receptor does. (Fig. 24.3) Unlike the and S-receptors that bind the (enkephalin) peptide sequence Tyr-Gly-Gly-Phe-(Leu Met), the K-receptor does not. The K-receptor shows a clear preference for binding peptides with an arginine in position 6 as seen in the dynor-phin peptides (Fig. 24.2).45 The structure of some K-agonists and an antagonist...

Orange zone when a solution in concentrated nitric acid is stratified under ammonia. Almost all so-called alkaloidal reagents will precipitate proteins in slightly acid solution. The qualitative identification of the amino acids found in proteins and other substances has been simplified greatly by the application of paper chromatographic techniques to the proper hydrolysate of proteins and related substances. End-member degradation techniques for the detection of the sequential arrangements of...

Sodium pertechnetate (99mTc) is a sterile, colorless solution in normal saline (0.9 NaCl), obtained by elution of the sterile Mo-99 Tc-99m generator. The major use of sodium pertechnetate (99mTc) is the preparation of various technetium-99m radiopharmaceu-ticals either in a nuclear pharmacy or nuclear medicine department. On-site preparation of radiolabeled red blood cells (RBCs) requires the availability of sodium pertechnetate since the radiolabeled cells must be...

Vitamin A belongs to a class of compounds referred to as the retinoids, which consist of four isoprenoid units joined in a head-to-tail manner.20 All double bonds in the isoprenoid units are implied to be in the E (trans) configuration unless stated otherwise. Currently, the term retinoid is applied to retinol and its naturally occurring derivatives plus synthetic analogs, which need not have vitamin A activity. Vitamin A is currently used as a generic descriptor for all retinoids that exhibit...

Amino acid solutions contain a mixture of essential and nonessential crystalline amino acids, with or without electrolytes (e.g., Aminosyn, ProcalAmine, Travasol, Novamine). Although oral studies have shown a comparison between protein hydrolysates and free amino acid diets,2 protein hy-drolysates are being replaced by crystalline amino acid solutions for parenteral administration because the free amino acids are used more efficiently than the peptides produced by the enzymatic cleavage of...

In addition to their inhibition of mediator release, some of these drugs also inhibit the chemotaxis of eosinophils at the site of application (i.e., ocular tissue).54 In lung tissue, pretreatment with the mast cell stabilizers cromolyn and ne-docromil blocks the immediate and delayed bronchocon-strictive reactions induced by the inhalation of antigens. These drugs also attenuate the bronchospasm associated with exercise, cold air, environmental pollutants, and certain drugs (aspirin). However,...

Figure 16.18 Metabolism of acebutolol. Carvedilol. Carvedilol (Coreg) is a -blocker that has a unique pharmacological profile. Like labetalol, it is a -blocker that possesses arblocking activity. Only the (S) enantiomer possesses the -blocking activity, although both enantiomers are blockers of the -receptor.64 Overall, its -blocking activity is 10- to 100-fold of its a-blocking activity. This drug is also unique in that it possesses antioxidant activity and an antiproliferative effect on...

Hydromorphone, (Dilaudid) is a synthetic derivative of morphine prepared by the catalytic hydrogenation and dehy-drogenation of morphine under acidic conditions, using a large excess of platinum or palladium.63 Oxidation of the 6-OH of morphine resulted in a compound with decreased potency. Reducing the 7,8 double bond of morphine increased the flexibility of the molecule and resulted in a compound with slightly enhanced binding. Making both of these structural changes to morphine-produced...

Naltrexone (Fig. 24.13) is a pure opioid antagonist at all opioid receptor subtypes with the highest affinity for the -receptor. Naltrexone is orally bioavailable and blocks the effects of opiate agonists for approximately 24 hours after a single dose of 50 mg. It produces no opioid agonist effects and is devoid of any intrinsic actions other than opioid receptor blockade. Theoretically, it should work well to treat opioid dependence but in clinical practice, patients have shown poor compliance...

Nalmefene (Revex) is a pure opioid antagonist that is the 6-methylene analog of naltrexone. It is available as a solution for IV, IM, or subcutaneous (SC) administration to reverse the effects of opioids after general anesthesia and in the treatment of overdose. It is longer acting than nalox-one but otherwise has a similar pharmacodynamic and metabolic (3-glucuronidation) profile. Nalmefene has higher oral bioavailability (approximately 40 )123 than naloxone or naltrexone and is currently...

Acetaminophen (also known as paracetamol, APAP), a well established analgesic antipyretic drug, is frequently used by itself OTC (Panado, Tempra, Tylenol) or in combination with codeine (Tylenol 3), hydrocodone (Vicodin), or oxy-codone (Percocet) for the treatment of mild to moderate pain and to reduce fever. It is available in several nonprescription forms and is also marketed in combination with aspirin and caffeine (Excedrin, Vanquish). Unlike aspirin or ibuprofen, acetaminophen is well...

Hib causes the most common type of bacterial meningitis and is a major cause of systemic disease in children younger than 6 years old. The chances of contracting the disease are about 1 in 200. Of these contractees, 60 of all patients develop meningitis, while 40 display systemic signs. Hib is a tremendous problem in daycare centers, where the risk of contracting the disease is 400 times greater than in the general population. Hib has approximately a 10 mortality rate, and one third of all...

A theory of blood clotting introduced in 1905 was based on the existence of four factors thromboplastin (thrombokinase), prothrombin, fibrinogen, and ionized calcium. The clotting sequence proposed was that when tissue damage occurred, thromboplastin entered the blood from the platelets and reacted with prothrombin in the presence of calcium to form thrombin. Thrombin then reacted with fibrinogen to form insoluble fibrin, which enmeshed red blood cells (RBCs) to create a clot. The concept...

There are two distinct estrogen receptors (ERs), estrogen receptor a (ERa) and estrogen receptor 3 (ER3), which are encoded by different genes.11 The ERs have distinct tissue distributions and can have distinct actions on the target genes. ER can be found in high abundance in the uterus, vagina, and ovaries, as well as in the breast, the hypothalamus, endothelial cells, and vascular smooth muscle. ER3 is found in greatest abundance in the ovaries and the prostate, with reduced occurrence in the...

These are perhaps the most widely used drugs worldwide because three members of this class, ibuprofen, naproxen, and ketoprofen, are now available without a prescription (Fig. 24.19). Their indiscriminate use, however, by the general public without a doctor's prescription, has resulted in an increased incidence of complications in adolescents, including acute and chronic renal failure.185 All of the members of this class (except oxaprozin) contain a chiral carbon in the a-position of the acetic...

PD is a progressive neurodegenerative illness characterized by tremor, muscular rigidity, bradykinesia (slowness of movement), and postural imbalance.8 The incidence of PD is estimated to be about 1 in the general population older than 60 years of age.9 Although characterized as a neuro-muscular disorder, dementia also occurs at a much greater rate in PD patients over the normal age-matched population.10 Although the etiology of PD remains unknown, several factors appear to play a role,...

As an alternative to utilizing aziridines as electrophilic species, it was found that simply utilizing a carbon chain terminated at both ends by leaving groups gave compounds capable of acting as cross-linking agents (Scheme 10.9).19 Busulfan utilizes two sulfonate functionalities as leaving groups separated by a four-carbon chain that reacts with DNA to primarily form intrastrand cross-link at 5'-GA-3' sequences.20 The sulfonates are also subject to displacement by the sulfhydryl functions...

Immunity in humans can be conceptualized in several different ways. If just the type and specificity of the immune response are considered, the ideas of innate and acquired immunity are used. If only the components that are involved in the immune response are considered, the processes can be divided into humoral and cellular immunity. If the location of the immune response is considered, we find that the immune system consists of serosal (in the serum) immunity and mucosal (on mucosal...

Meperidine (Demerol) (Fig. 24.9) was discovered in 1939 during a serendipitous screening of compounds being studied for antispasmodic activity. Mice given meperidine were noted to carry their tails in an erect position (the Straub tail reaction), which was indicative of narcotic analgesia. This led to the study of meperidine and derivatives as analgesic agents. Meperidine was found to have low potency at the receptor compared with morphine (0.2 ) but much higher penetration into the brain...

The diagnosis of a first epileptic seizure or epilepsy, at primary care facilities, is often subjective and prone to error because it is usually based on eyewitness accounts of the episodes.6,12 An incorrect diagnosis, especially of the seizure type, however, can have far-reaching negative consequences for the patient, including loss of work and driving privileges, potential toxic or ineffective medication given, and other socioeconomic consequences.13 Classification of Epileptic Seizures and...

Inorganic acids, like organic acids, will form esters with an alcohol. Pharmaceutically, the important ones are sulfate, nitrite, and nitrate. Sulfuric acid forms organic sulfates, of which methyl sulfate and ethyl sulfate are examples. Nitrous acid (HNO2) esters may be formed readily from an alcohol and HNO2. The usual procedure is to mix sodium nitrite, sulfuric acid, and the alcohol. Organic nitrites are generally very volatile liquids that are only slightly soluble in water but soluble in...

Another approach to developing new therapies based on the known biological activities of the prostaglandins and leukotrienes requires characterization of the naturally occurring tissue receptors for these agents. A thorough knowledge of the tissue distribution (localization) of such receptors and their binding characteristics would allow the design of receptor-specific agonists or antagonists, which might not possess the same limitations as the natural eicosanoids, but could affect tissue...

Gastrin is a 17-residue polypeptide isolated from the antral mucosa. It was isolated originally in two different forms. In one of the forms, the tyrosine residue in position 12 is sul-fated. Both forms are biologically active. Cholinergic response to the presence of food in the gastrointestinal tract provides the stimulus for gastrin secretion. The lowering of pH in the stomach inhibits the secretion of gastrin. The effects of structural modification of gastrin on gastric acid secretion have...

Two prospective clinical studies using dried whole feverfew leaf have been performed33'34 to assess the value of the herb in migraine. The two leaf studies on migraine provided good supportive evidence for activity of the herb against migraine. Both studies were double-blinded, placebo-controlled, and standardized on 0.54-mg parthenolide per capsule. In both studies, the feverfew group demonstrated significant decreases in frequency, severity of attacks, and nausea and vomiting. No adverse...

Hypertension is a consequence of many diseases. Hemodynamically, blood pressure is a function of the amount of blood pumped by the heart and the ease with which the blood flows through the peripheral vasculature (i.e., resistance to blood flow by peripheral blood vessels). Diseases of components of the central and peripheral nervous systems, which regulate blood pressure and abnormalities of the hormonal system, and diseases of the kidney and peripheral vascular network, which affect blood...

Cardiac arrhythmias are caused by a disturbance in the conduction of the impulse through the myocardial tissue, by disorders of impulse formation, or by a combination of these factors. The antiarrhythmic agents used most commonly affect impulse conduction by altering conduction velocity and the duration of the refractory period of heart muscle tissue. They also depress spontaneous diastolic depolarization, causing a reduction of automaticity by ectopic foci. Many pharmacological agents are...

Table 28.7 is a list of the currently available products, and Figure 28.10 shows their structures. Most vitamin supplements containing vitamin D singly, or in combination with other vitamins as multivitamin preparations, contain chole-calciferol. However, ergocalciferol can also be used These are available in various preparations under many different names as oral capsules, tablets, solutions, and powders. Table 28.7 also shows the vitamin D analogs used in the treatment of renal osteodystrophy...

The immune system constitutes the body's defense against infectious agents. It protects the host by identifying and eliminating or neutralizing agents that are recognized as nonself. The entire range of immunological responses affects essentially every organ, tissue, and cell of the body. Immune responses include, in part, antibody (Ab) production, allergy, inflammation, phagocytosis, cytotoxicity, transplant and tumor rejection, and the many signals that regulate these responses.1 At its most...

Figure 16.6 Mechanism of a-i-receptor-mediated signal transduction. Figure 16.6 Mechanism of a-i-receptor-mediated signal transduction. receptors that are linked to stimulation of biochemical processes in the postsynaptic cell. The function of presynaptic jS-receptors is, however, unclear. The jS-adrenoceptor subtypes also differ in terms of the rank order of potency of the adrenergic receptor agonists NE, E, and ISO (Table 16.4). The use of jS2-agonists as bronchodilators and jS 1- or Si...

Over the past decade and a half, far-reaching and revolutionary breakthroughs in molecular biology, especially research involving gene manipulations (i.e., genetic engineering), have led the way in the development of new biotechnology-derived products for the treatment of diseases. The term biotherapy has been coined to describe the clinical and diagnostic use of biotechnology-derived products. Generally, these products are proteins, peptides, or nucleic acids that are structurally and or...

&lt alendronate &lt pamidronate &lt zoledronate (highest). As noted in later discussion, this order does not completely parallel antiresorptive potency. A key difference between the non-N-containing and N-containing bisphosphonates is the ability of the latter to form positive charges on their nitrogens at physiological pH. In general, the more positively charged bisphosphonates (zoledronate, ibandronate, and alendronate) produce a positive surface on the bone, attracting additional...

Whereas estrogens have been very important in chemical contraception and HRT, compounds that can antagonize the ER have been of great interest for the treatment of estrogen-dependent breast cancers. Tumor biopsies have shown ER to be present in about 60 of primary breast cancers, and most are responsive to estrogen blockade. Unfortunately, most of these ER-related breast cancers also develop resistance to antiestrogen therapy within 5 years. In contrast, only about 6 of nonmalignant breast...

Isoflurane is a volatile liquid (bp 48.5 C) with an MAC of 1.15, a blood gas partition coefficient of 1.43 and high solubility in fat. Isoflurane is a structural isomer of enflurane. It is a known respiratory irritant, but less so than desflurane. Approximately 0.2 of the administered drug undergoes metabolism, the rest is exhaled unchanged. The metabolism of isoflurane yields low levels of the nephrotoxic fluoride ion as well as a potentially hepatotoxic trifluoroacetylating compound (Fig....

Enflurane is a volatile liquid (bp 56.5 C) with a blood gas partition coefficient of 1.8 and an MAC of 1.68 . Approximately 2 to 8 of the drug is metabolized primarily at the chlorofluoromethyl carbon. Little chlorofluo-roacetic acid is produced suggesting minor metabolism at the difluoromethyl carbon. Difluoromethoxydifluoroacetate and fluoride ion have been reported as metabolites. Enflurane may increase heart rate, cause cardiac arrhythmias, increase cerebral blood flow, and increase...

As discussed, work of Meyer and Overton in the 1880s showed that there was strong correlation between the potency of the anesthetic and its solubility in olive oil. This correlation holds true for a surprising number of inhaled anesthetics but it does not explain the drugs mechanism of action. When biological membranes were found to be composed mainly of lipids, the work of Meyer and Overton was extended to offer a proposed mechanism of action of the inhaled anesthetics. Namely, that the...

The most notable achievement in chemical contraception came in the late 1950s and early 1960s with the development of oral contraceptive agents the pill. Since then, various contraceptive products have been introduced, including hormone-releasing intrauterine devices, polymer implants, injectable formulations, and a transdermal patch. In addition, postcoital contraceptives and abortifacients have been developed. Despite the advances in chemical contraceptive agents for women, no hormonal male...

Nicotinic receptors located in the neuromuscular junction differ from those on neurons, such as those in the CNS and autonomic ganglia, in that they have different ligand specificities. Nicotinic receptors at the neuromuscular junction (N1) are blocked by succinylcholine, d-tubocurarine, and decamethonium and stimulated by phenyltrimethylammo-nium. N2-nicotinic receptors are found in autonomic ganglia. They are blocked by hexamethonium and trimethaphan but stimulated by tetramethylammonium and...

Figure 22.4 Sevoflurane metabolism and chemical instability. Approximately 5 to 8 of the administered dose of sevoflurane is metabolized in man by CYP2E1 to hexafluo-roisopropanol, CO2 and the potentially nephrotoxic fluoride ion. (Fig. 22.4).27,30,31 Patients should be monitored for increases in blood urea nitrogen (BUN) and creatine levels as high fluoride ion levels, and concerns about Compound A exposure, may induce renal toxicity. Sevoflurane has been studied in a small number of patients...

Portions of this text were taken from Dr. Eugene Isaacson's chapter in the 11th edition of this book. 1. What is the mechanism of action of the benzodiazepines 2. What is the mechanism by which antipsychotics work 3. What pharmacokinetic properties are shared by most of the antipsychotic drugs 4. Which benzodiazepines shown below is are short acting 5. Which of the following drugs is are metabolized to a compound that will continue to have significant sedative and hypnotic effect

Of the various phase I reactions that are considered in this chapter, oxidative biotransformation processes are, by far, the most common and important in drug metabolism. The TABLE 3.2 Cytochrome P450 Enzymes Nomenclature CYP-Arabic Number-Capital Letter-Arabic Number 1. CYP Cytochrome P450 enzymes 2. Arabic number Family (CYP1, CYP2, CYP3, etc.) Must have more than 40 identical amino acid sequence 3. Capital letter Subfamily (CYP1A, CYP2C, CYP3A, etc.) Must have more than 55 identical amino...

Class I antiarrhythmic agents are drugs that have membrane-stabilizing properties (i.e., they shift membranes to more negative potentials). Drugs in this class act on the fast Na+ channels and interfere with the process by which the depolarizing charge is transferred across the membrane. It is assumed that these drugs bind to the Na+ channel and block its function, preventing Na+ conductance as long as the drug is bound. The prototypical drugs in this class are quinidine and procainamide....

Figure 17.17 Aging of phosphorylated enzyme. Figure 17.17 Aging of phosphorylated enzyme. these poisons. Several compounds can provide a nucleophilic attack on the phosphorylated enzyme and cause regeneration of the free enzyme. Substances such as choline, hydroxyl-amine, and hydroxamic acid have led to the development of more effective cholinesterase reactivators, such as nicotinic hydroxamic acid and pyridine-2-aldoxime methiodide (2-PAM). A proposed mode of action for the reactivation of...

Drugs in this class (e.g., amiodarone, bretylium, sotalol, ibu-tilide, dofetilide) cause several different electrophysiologi-cal changes on myocardial tissue but share one common effect, prolonging the action potential, which increases the effective refractory period of the membrane action potential without altering the phase of depolarization or the resting membrane potential. Drugs in this class produce their effects by more than one mechanism. Sotalol is a K+ channel blocker and has some...

Since Alexander Fleming accidentally discovered penicillin in 1929, the numbers of antibiotics that have been added to our therapeutic armamentarium has grown tremendously. Along with immunizing biologicals, antibiotics have turned the tide in terms of the treatment of infectious disease. They are truly medical miracles. Yet, because of the overuse of many of these agents and the biochemical fickleness of many bacteria, resistance to antibiotics has become a serious problem in the 21st century....

Nalbuphine (Nubain) is structurally a member of the phenanthrene class of compounds and resembles oxymor-phone with a cyclobutyl methyl group on the nitrogen, equivalent to naloxone's substitution. It was introduced in 1979 as an agonist antagonist with the hope of becoming an effective pain reliever with little abuse potential. Although the abuse potential of nalbuphine is low, it is not zero, and increasing reports of diversion and abuse can be found in the literature and the Internet.105 At...

Figure 12.10 Major metabolic pathway for aripiprazole. Ziprasidone. Ziprasidone (Geodon, a benzisothia-zolpiprazinylindolone derivative) also has the structural features of a hybrid molecule between a butyrophenone antipsychotic and a trazodone-like antidepressant. It is highly metabolized to four major metabolites, only one of which, S-methyldihydroziprasidone, likely contributes to its clinical activity (see Fig. 12.9). In humans, less than 5 of the dose is excreted unchanged. Reduction by...

Figure 24.15 Hypothetical binding models of indomethacin to COX-1 and Celecoxib to COX-2. A. Binding of the conventional NSAID, indomethacin, to the active site of COX-1 B. Binding of celecoxib, a selective COX-2 inhibitor to the active site of COX-2 with crystallographic maps suggested by Luong et al. (Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat. Struct. Biol. 1996 3 927-933)

Thiamine diphosphate Figure 28.20 Thiamine and thiamine diphosphate. a common form available for vitamin supplementation, is stable in acid but unstable in aqueous solutions with a pH above 5. Under these conditions, it undergoes decomposition of the thiazolium ring forming an inactive product (Fig. 28.22). Exposure of thiamine to air or to oxidizing agents such as hydrogen peroxide, permanganate, or alkaline potassium ferricyanide oxidizes it readily to thiochrome (Fig. 28.23). Thiochrome...

Sevoflurane is a volatile, nonpungent, nonflammable, and nonexplosive liquid with a boiling point of 58.6 C. The blood gas partition coefficient is 0.65, the oil gas partition coefficient is 50, and the MAC is 2.1 . Sevoflurane reacts with desiccated carbon dioxide adsorbents, to produce compounds (A and B) with known toxicity (Fig. 22.4). The type of CO2 absorbent used, the temperature of the absorbent, and the duration of exposure can influence the degree to which sevoflurane breaks down.25...

EC 1.4.3.5 pyridoxal 5'-phosphate synthase EC 2.7.1.35 pyridoxal kinase EC 3.1.3.74 pyridoxal phosphatase EC 1.2.3.1 aldehyde oxidase a cotransaminase in the transamination of alanine to form pyruvic acid and as a codecarboxylase in the decarboxylation of dihydroxyphenylalanine (DOPA) to form dopamine. Other biological transformations of amino acids in which pyridoxal can function are racemization, elimination of the -hydrogen together with a -sub-stituent (i.e., OH or SH) or a y-substituent,...

RECOMBINANT HUMAN DEOXYRIBONUCLEASE I (DNASE)143 DNAse is a human endonuclease, normally present in saliva, urine, pancreatic secretions, and blood. The enzyme catalyzes the hydrolysis of extracellular DNA into oligonu-cleotides. Aerosolized recombinant human deoxyribonu-clease I (rhDNAse), dornase alfa, Pulmozyme, has been formulated into an inhalation agent for the treatment of pulmonary disease in patients with CF. Among the clinical manifestations of CF are obstruction of the airways by...

Niacin synthesis into the active cofactors, NAD+ and NADP+, is shown in Figure 28.29. Both niacin and niacinamide react with 5-phosphoribosyl-1-pyrophosphate (PRPP) to form the respective mononucleotide derivative, which then reacts with ATP to produce the corresponding dinucleotide product. For niacinamide, this is NAD + however, for niacin this product is converted to NAD+ by transformation of the carboxyl of the nico-tinic acid moiety to the amide using free ammonia. An alternative pathway...

Protamine sulfate has an anticoagulant effect, but if used in the proper amount, it counteracts the action of heparin and is used as an antidote for the latter in cases of overdosage. It is administered intravenously in a dose that depends on the circumstances. Dicumarol, USP. Dicumarol, 3,3'-methylenebis 4-hy-droxycoumarin , is a white or creamy white crystalline powder with a faint, pleasant odor and a slightly bitter taste. It is practically insoluble in water or...

Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Edition, includes additional resources for both instructors and students that are available on the book's companion Web site at Approved adopting instructors will be given access to the following additional resources Image bank of all the figures and tables in the book Students who have purchased Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Edition, have access to the...

The sulfate esters and sulfonate derivatives of polysaccha-rides and lignin form chemical complexes with the enzyme pepsin. These complexes have no proteolytic activity. Because polysulfates and polysulfonates are poorly absorbed from the GI tract, specific chemical complexation appears to be a desirable mechanism of pepsin inhibition.77 Unfortunately, these polymers are also potent anticoagulants. The properties of chemical complexation and anticoagulant action are separable by structural...

The benzamides evolved from observations that the gastro-prokinetic and antiemetic agent, metoclopramide, has an-tipsychotic activity related to D2 receptor block. It was hoped that the group might yield compounds with diminished EPS liability. This expectation appears to have been met. An H-bond between the amido H and the unshared electrons of the methoxyl group to generate a pseudo ring is considered important for antipsychotic activity in these compounds. Presumably, when the protonated...

Folic acid, and dietary forms of folate that are not in the reduced state, must undergo reduction of ring B for biological activity. Folic acid is first reduced to H2PteGlu by dihydrofolate reductase (DHFR EC 1.5.1.3) using NADPH as a cofactor and then to H4PteGlu by the same enzyme. These key steps are important in the understanding of the folate antagonists, such as methotrexate, that inhibit DHFR and, thereby, interfere with the utilization of all folates that are not in the reduced...

Bupivacaine was synthesized simultaneously with mepiva-caine in 1957 but was at first overlooked because of the increased toxicity compared with mepivacaine. When the methyl on the cyclic amine of mepivacaine is exchanged for a butyl group the lipophilicity, potency and the duration of action all increase. Literature reports of cardiovascular toxi-city, including severe hypotension and bradycardia, are abundant in the literature.91 Bupivacaine is highly bound to plasma proteins (95 ), and thus...

Aldosterone antagonists are, as the name implies, receptor antagonists at the mineralcorticoid receptor. Antagonism of these receptors inhibits sodium resorption in the distal tubule of the nephron, which in turn, interferes with sodium potas sium exchange, reducing urinary potassium excretion. Overall, this results in a weak diuretic effect and decreases cardiac workload. Agents that block aldosterone may be used in the management of hypertension or heart failure. The two agents approved for...

Tuberculosis (TB) is a serious disease caused by Mycobacterium tuberculosis. The organism becomes established in the lungs and forms walled-off abscesses that shield the bacterium from the immune system. The disease is diagnosed by a chest radiograph. Until the 1940s, persons with TB were sent to sanatoria, special hospitals to isolate TB patients. The vaccine is referred to as the bacillus Calmette-Guerin (BCG) vaccine and is a live attenuated strain of Mycobacterium bovis. The antigenic form...

Vascular smooth muscle cells to form nitric oxide (NO). NO mediates smooth muscle relaxation by activating guanylate cyclase to increase intracellular concentrations of cGMP. cGMP activates protein kinases that can regulate free Ca2+ levels in the muscle cell and cause relaxation of smooth muscle by phosphorylating MLCK. A short-lived free radical gas, NO is widely distributed in the body and plays an important role by its effect through cGMP on the smooth muscle vasculature. It is synthesized...

Indium (111In) Capromab (ProstaScint). Capromab pendetide is a murine monoclonal immunoglobulin G (IgG) antibody conjugated to the linker-chelator, glycyl-tyrosyl-(N,-diethylenetriamine pentaacetic acid)-lysine hydrochloride (Gly-Tyr-Lys-DTPA-HCl). This conjugated antibody is directed against the glycoprotein expressed on prostate epithelium, prostate-specific membrane antigen. It is indicated in the evaluation of newly diagnosed patients with biopsy-proven prostate cancer who are at high risk...

5'-Hydroxymethylmeloxicam, R CH2OH, 5'-Carboxymeloxicam, R COOH Figure 24.16 Metabolism of Piroxicam and meloxicam. 5'-hydroxy-methylmeloxicam and 5'-carboxymeloxicam metabolites are shown in Figure 24.16.154-156 Thus, with the proposed binding interaction of indomethacin described earlier (Fig. 24.15), it is reasonable to assume that the pyridyl group of the piroxicam or the 5'-hydroxy-pyridyl group of its active metabolite will be directed to bind to the A11-double-bond binding region...

Genomics177 is a term that means a study of genes and their functions. Currently, genomics is probably the central driving force for new drug discovery and for novel treatments for disease. Gene therapy is a concept that is often discussed. The human genome project, which was largely completed in the year 2000, provided over 4 billion bp of data that have been deposited in public databases. Sequencing the genome itself was an enormous task, but the correlation of genomic data with disease...

With few exceptions, the steroids are white crystalline solids. They may be in the form of needles, leaflets, platelets, or amorphous particles, depending on the particular compound, the solvent used in crystallization, and the skill and luck of the chemist. Because the steroids have 17 or more carbon atoms, it is not surprising that they tend to be water insoluble. Addition of hydroxyls or other polar groups (or decreasing carbons) increases water solubility slightly, as expected. Salts are...

Opioid Receptor Discovery and Endogenous Ligands There was no direct evidence for the existence of specific opioid receptors until the 1970s when Goldstein et al.20 found that radiolabeled levorphanol bound stereospecifi-cally to certain mouse brain fractions. They hypothesized that this compound bound to an opiate receptor. This prediction gained credence in 1973 when additional studies showed that opioid agonists and opioid antagonists compete for the same binding site. Building on these...

Cefuroxime is distributed throughout the body. It penetrates inflamed meninges in high enough concentrations to be effective in meningitis caused by susceptible organisms. Three-times-daily dosing is required to maintain effective plasma levels for most sensitive organisms, such as Neisseria meningitidis, Streptococcus pneumoniae, and H. influenzae. It has a plasma half-life of 1.4 hours. Cefuroxime axetil (Ceftin) is the 1-acetyoxyethyl ester of cefuroxime. During absorption, this acid-stable,...

Steroid hormones in mammals are biosynthesized from cholesterol, which in turn is made in vivo from acetyl-coenzyme A (acetyl-CoA) via the mevalonate pathway. Although humans do obtain approximately 300 mg of cholesterol per day in their diets, a greater amount (about 1 g) is biosynthesized per day. A schematic outline of these biosynthetic pathways is shown in Figure 25.5. Conversion of cholesterol to pregnenolone is the rate-limiting step in steroid hormone biosynthesis. It is not the...

Hydrocodone is the 3 methoxy version of hydromorphone. The loss of the 3-OH group yields a compound that is approximately 4 to 5 times less potent than hydromorphone, thus about equal to morphine. Unlike codeine, the agonist activity of hydrocodone does not require 3-O-demethylation, although it does occur via CYP2D6 representing 4.6 of total clearance.64 The protected 3-position has better brain penetration, and the 7,8-dihydro-6-keto C ring contributes to the increased binding of the compound...

or N-ethyl-o-crotonotoluidide (Eurax), is a colorless, odorless oily liquid. It is virtually insoluble in water but soluble in most organic solvents. Its antipruritic effect is probably because of a local anesthetic action. Permethrin is acid (3-phenoxyphenyl)methyl ester or 3-(phenoxyphenyl)methyl ( )-cis, (Nix). This synthetic pyrethrinoid compound is more stable chemically than most natural pyrethrins and is at least as active as an insecticide. Of the four isomers present, the 1(R),trans...

The National Asthma Education and Prevention Program has provided recent recommendations on the treatment of asthma, including a strong recommendation for the first-line use of inhaled corticosteroids for severe and moderate persistent asthma in all age groups. The corticosteroids currently used in inhaled formulations are all relatively potent topical corticos-teroids that have the advantage of rapid deactivation inactiva-tion for the portion of the dose that is swallowed. The development of...

Ibritumomab (Zevalin kits to prepare In-111 Zevalin and Y-90 Zevalin, murine) is an MAb derived from an initial sen-sitization with CD20 antigen, expressed on the surface of normal and malignant B cells. The antibody is a murine IgG1 k subtype, directed against CD20 antigen. It is produced in a CHO cell line. Ibritumomab is indicated for use as a multistage regimen to treat patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma, including patients...

Tamoxifen, A-dimethylethanamine (Nolvadex), is a triphenylethylene SERM used to treat early and advanced breast carcinoma in postmenopausal women. Tamoxifen is used as adjuvant treatment for breast cancer in women following mastectomy and breast irradiation. It reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy. It is also effective in the treatment of metastatic breast cancer in both women and men. In premenopausal...

For 6 decades, Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry has been a standard in the literature of medicinal chemistry. Generations of students and faculty have depended on this textbook not only for undergraduate courses in medicinal chemistry but also as a supplement for graduate studies. Moreover, students in other health sciences have found certain chapters useful. The current editors and authors worked on the 12th edition with the objective of...

According to the vascular theory, the vasodilatation of cranial carotid arteriovenous anastomoses (sites of many 5-HT1B 1D receptors) and meningeal, dural, cerebral, or pial vessels (primary sites of 5-HT1B receptors) plays an important role in the pathogenesis of migraines and is responsible for the pain associated with migraine headaches.259,261 The fact that sumatriptan-induced cranial vasoconstriction is selectively blocked by a selective 5-HT1B antagonist, and not by a 5-Ht1D antagonist,...

Niacin, in doses that range above the DRI but below that required for dyslipidemias, is unlikely to produce adverse effects. However, adverse effects of niacin are seen when this vitamin is used at pharmacological doses above 1 g day in the treatment of dyslipidemia. Notable adverse effects include flushing because of vasodilation dermatological effects including dry skin, pruritus and hyperkeratosis gastrointestinal effects including peptic ulcer, stomach pain, nausea, and diarrhea elevations...

The contractile activity of all types of muscle (smooth, skeletal) is regulated primarily by the reversible phosphorylation of myosin. Myosin of smooth muscle consists of two heavy chains (molecular weight MW 200,000 each) that are coiled to produce a filamentous tail. Each heavy chain is associated with two pairs of light chains (MW 20,000 and 16,000) that serve as substrates for calcium- and calmodulin-dependent protein kinases in the contraction process. Together with actin (MW 43,000), they...

Most coronary artery disease conditions are caused by deposits of atheromas in the intima of large and medium-sized arteries serving the heart. The process is characterized by an insidious onset of episodes of cardiac discomfort caused by ischemia from inadequate blood supply to the tissues. Angina pectoris (angina), the principal symptom of ischemic heart disease, is characterized by a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the...

Hydrolytic reactions of the peptide bonds can break the polymer chain. Aspartate residues hydrolyze 100 times faster in dilute acids than do other amino acids under the same conditions. As a general rule of peptide hydrolysis, Asp-Pro &gt Asp-X or X-Asp bonds. This property of Asp is probably a result of an autocatalytic function of the Asp side chain carboxyl group. Asn, Asp, Gln, and Glu hydrolyze exceptionally easily if they occur next to Gly, Ser, Ala, and Pro. Within these...

The effects of the azoles on fungal biochemistry have been studied extensively, but there is still much to be learned.45 At high in vitro concentrations (micromolar), the azoles are fungicidal at low in vitro concentrations (nanomolar), they are fungistatic. The fungicidal effect is clearly associated with damage to the cell membrane, with the loss of essential cellular components such as potassium ions and amino acids. The fungistatic effect of the azoles at low concentration has been...

The tools of biotechnology are also being brought to bear in the search for new biological targets for presently available drugs as well as for the discovery of new biological molecules with therapeutic utility. Molecular cloning of novel receptors can provide access to tremendous tools for the testing of drugs (e.g., the adrenergic receptors), whereas cloning of a novel growth factor might potentially provide a new therapeutic agent. Biotechnology is also being used to screen compounds for...

Elemental iodine (I2) is probably the oldest germicide still in use today. It was listed in 1830 in USP-II as a tincture and a liniment. Iodine tincture (2 iodine in 50 alcohol with sodium iodide), strong iodine solution (Lugol's solution, 5 iodine in water with potassium iodide), and iodine solution (2 iodine in water with sodium iodide) are currently official preparations in the USP. The iodide salt is admixed to increase the solubility of the iodine and to reduce its volatility. Iodine is...